Parallel Solid-Phase Synthesis and Structural Characterization of a

Oct 12, 2000 - Cleavage of the oxazolidines from the resin support was achieved with TBAF to give the individual members (2R,4R,5R)-5Aaa-Cdd and (2S,4...
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J. Comb. Chem. 2000, 2, 698-709

Parallel Solid-Phase Synthesis and Structural Characterization of a Library of Highly Substituted Chiral 1,3-Oxazolidines Martin R. Tremblay, Paul Wentworth, Jr.,* George E. Lee, Jr.,† and Kim D. Janda* Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037 ReceiVed June 14, 2000 The rapid parallel synthesis and characterization of diverse chirally defined 1,3-oxazolidines is reported. Three diversity elements were incorporated in a 6 × 4 × 4 block approach to generate a 96-member 1,3oxazolidine library. The synthetic route involved initial attachment of six nonracemic phenylglycidols, (2S,3S)1A-C and (2R,3R)-2A-C, to 2% cross-linked polystyrene resin via a chlorodiethylsilane linker (PS-DES), followed by regio- and stereoselective oxirane ring opening with four primary amines (3a-d). The key condensation reaction between the resulting polymer-bound β-amino alcohols and four aldehydes (4a-d) was found to occur optimally in warm benzene (60 °C) in the presence of anhydrous magnesium sulfate. Cleavage of the oxazolidines from the resin support was achieved with TBAF to give the individual members (2R,4R,5R)-5Aaa-Cdd and (2S,4S,5S)-6Aaa-Cdd in good to excellent yields (51-99%) based on mass recovery. Purities of all these crude products was generally >85% (as measured by LCMS). 1H, 13C NMR, and 1D difference nOe of the library members confirmed the structural and stereochemical integrity of the substituents around the 1,3-oxazolidine core. The asymmetric induction at C-2 (cis or trans to the C-4 substituent) ratio ranged from 4 to 1 to 49 to 1 across the library. This report highlights the versatility of the 1,3-oxazolidine heterocycle as a scaffold for concise parallel library construction and opens the way for high-throughput screening of such compounds in the biological sphere. Introduction Initial combinatorial strategies, driven by both existing solid-phase methodology and known pharmacophoric structures, focused on oligomeric materials such as peptides,1-3 nucleotides,4 and oligosaccharides.5 However, the poor pharmacokinetic profile of such oligomeric materials has meant that most of today’s therapeutic agents are small molecules, and therefore present combinatorial efforts are evolving toward libraries of such derivatives.6,7 An approach receiving increasing interest is molecular scaffolding, whereby the synthesis of libraries of compounds occurs on multiply substituted templates that can be selectively and sequentially functionalized. Early templates included purine and triazine structures,8-10 monosaccharides,11-13 and polycarboxylic acids.14,15 In this paper we describe the 1,3-oxazolidine heterocycle as a new scaffold for library synthesis. 1,3-Oxazolidines are remarkably versatile molecules having found use as chiral auxiliaries,16,17 as intermediates for more complex chiral heterocycles,18-22 and as prodrugs for improving the pharmacokinetic profile of certain β-amino alcohol pharmacophores.23 They are ideally suited as scaffolds for combinatorial library generation because they have a rigid core that possesses four sites for the incorporation of diversity elements and can be synthesized with a high degree * Corresponding authors. P.W.: telephone (858) 784-2476; fax (858) 784-2590; e-mail [email protected]. K.D.J.: telephone (858) 784-2515; fax: (858) 784-2595; e-mail [email protected]. † Structural and Physical Chemistry Dept., Aventis Research Center, Bridgewater, NJ.

Figure 1. (A) 1,3-Oxazolidine heterocycle showing the four sites available for diversification. (B) Our initial 1,3-oxazolidine library motif with three points of diversity R1-R3 at C-4, N-3, and C-2, respectively, and a linker appendage at C-5.

of chiral integrity (Figure 1A). We are exploring a systematic approach to the concise synthesis and characterization of chiral oxazolidine-based libraries, using nonracemic starting materials. Reported herein are our initial studies of the synthesis and characterization of chiral 1,3-oxazolidine libraries substituted at C-2, N-3, and C-4 (Figure 1B). Results and Discussion Library Design. The condensation of aldehydes with stereochemically defined β-amino alcohols under acidic conditions gives rise to oxazolidines where the cis-relationship between substituents at C-2 and C-4 predominates.17,24-27 This stereoselectivity arises from thermodynamic control imposed during ring closure that involves a rapid equilibrium via an open-chain iminium ion.28-30 We sought to exploit this known asymmetric induction at C-2 by coupling it with homochiral β-amino alcohol precursors such that the assembled 1,3-oxazolidines libraries possess high levels of diastereomeric purity. The general synthetic approach is shown in Scheme 1.

10.1021/cc0000500 CCC: $19.00 © 2000 American Chemical Society Published on Web 10/12/2000

Synthesis and Characterization of a 1,3-Oxazolidine Library

Scheme 1. (A) Synthetic Route to the (2R,4R,5R)-Oxazolidine Library 5Aaa-Cdd and (B) Synthetic Route to the (2S,4S,5S)-Oxazolidine Library 6Aaa-Cdda

a Reagents and conditions: (a) PS-DES resin (1.58 mmol/g), 1,3-dichloro5,5-dimethylhydandtoin (3 equiv), phenylglycidol 1A-C or 2A-C (3 equiv), imidazole (4 equiv), CH2Cl2, rt, 4 h; (b) resin-supported oxiranes (0.2-0.4 mmol), ethanol:amine (3a-d) (1:1) (2 mL), sealed tube, 70 °C, 48 h; (c) resin-supported β-amino alcohols, aldehyde (4a-d) (25 equiv), benzene, MgSO4, sealed tube, 60 °C; (d) resin-supported 1,3-oxazolidines, TBAF (1 M in THF, 3 equiv), THF, rt, 4 h.

Figure 2. Diversity elements R1, R2, and R3 incorporated into the 1,3-oxazolidine library 5Aaa-Cdd and 6Aaa-Cdd by means of a 6 × 4 × 4 block strategy. Substituted phenylglycidols 1A-C and 2A-C, primary amines 3a-d, and aldehydes 4a-d.

The first stage in library construction involved the utilization of nonracemic substituted trans 3-phenylglycidol derivatives (2S,3S)-1A-C and (2R,3R)-2A-C that incorporate both the first diversity element R1 and a locus for attachment to the resin support (Figure 2). Regio- and stereoselective ring opening of these derivatives31 is the key to establishing the chirality at C-4 (and hence C-2) and C-5 of the final oxazolidine library members. Furthermore, by exploiting enantiomeric epoxide antipodes (2S,3S)-1A-C and (2R,3R)2A-C as starting points for the synthesis, the diversity of a racemic mixture is coupled to the benefits of having enantiomerically pure final compounds.

Journal of Combinatorial Chemistry, 2000, Vol. 2, No. 6 699

Nonracemic phenylglycidols are available either commercially or via Sharpless epoxidation32 of the corresponding allylic alcohols. Initially we considered performing the Sharpless epoxidation on a resin-supported allylic alcohol. However, it has been reported that this reaction does not transfer well to heterogeneous conditions.33 Therefore, in the cases where the phenylglycidol could not be obtained commercially, the chiral epoxidation was performed routinely in solution. Selection of the amine and aldehyde building blocks, for incorporation of the R2 and R3 diversity elements, respectively, required optimization studies. The regio- and stereoselective opening of the glycidols (protected as their TBDMS ethers) in solution was shown to be a general reaction that was successful using either unbranched or branched aliphatic primary amines, benzylic amines, as well as anilines by utilizing Crotti’s method.34 As predicted,31 the primary amines attack the oxiranes at the benzylic carbon, as determined by 13C NMR and 1H NMR spectroscopy, to generate β-amino alcohols with almost complete regioselectivity (see Experimental Section). The condensation reaction between the β-amino alcohols and aldehydes to form 1,3-oxazolidines is acid-catalyzed; therefore, a number of conditions were explored, including solvent (EtOH, benzene, toluene, CHCl3, CH2Cl2), acids (PPTS, p-TSA, CH3SO2H), dehydrating agents (MgSO4, 4 Å molecular sieves), and temperature (25 °C and reflux). The mildest conditions applicable for the condensation reaction were found to be anhydrous MgSO4 in benzene at 60 °C. The optimization studies also refined the amines and aldehydes that could be incorporated into the library. Aromatic aldehydes were found to be unsuitable building blocks because they require particularly harsh condensation conditions (longer reaction times and higher temperatures) that concomitantly lead to product and starting material decomposition. In addition, anilines were discarded because the ring closure proceeds in both low yields and with poor discrimination of the two diastereoisomers at C-2. Therefore, it was ascertained that the ideal combination of building blocks was comprised of unbranched, branched aliphatic, or benzylic amines (3a-d) coupled with branched or unbranched aliphatic aldehydes (4a-d) (Figure 2). The next challenge was to establish a suitable linker strategy. Two important aspects were taken into consideration. While phenylglycidol 2A has previously been coupled to halo-substituted resins via the use of NaH with no evidence of chiral scrambling,35 a concern that glycidols 1B-C and 2B-C (R ) NO2 or Br) may be unstable to strong bases, being susceptible to the Payne rearrangement,36 meant that such conditions were avoided during attachment to the polymer. Furthermore, 1,3-oxazolidines are sensitive to acidic conditions, thus precluding the selection of acid-labile linkers such as Wang, Barlos,37 or Ellman’s38 which would be problematic during the cleavage step. Therefore we selected 2% cross-linked polystyrene derivatized with chlorodiethylsilane as the polymer support (PS-DES),39 rationalizing that cleavage with TBAF would be a suitably mild and orthogonal method.

700 Journal of Combinatorial Chemistry, 2000, Vol. 2, No. 6

Tremblay et al.

Table 1. Characterization of the (2R,4R,5R)-1,3-Oxazolidine Library 5Aaa-Cdd entry

R1

R2

R3

yielda/%

purityb/%

ratioc 2R:2S

5Aaa 5Aab 5Aac 5Aad 5Aba 5Abb 5Abc 5Abd 5Aca 5Acb 5Acc 5Acd 5Ada 5Adb 5Adc 5Add 5Baa 5Bab 5Bac 5Bad 5Bba 5Bbb 5Bbc 5Bbd 5Bca 5Bcb 5Bcc 5Bcd 5Bda 5Bdb 5Bdc 5Bdd 5Caa 5Cab 5Cac 5Cad 5Cba 5Cbb 5Cbc 5Cbd 5Cca 5Ccb 5Ccc 5Ccd 5Cda 5Cdb 5Cdc 5Cdd

H H H H H H H H H H H H H H H H NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 Br Br Br Br Br Br Br Br Br Br Br Br Br Br Br Br

benzyl benzyl benzyl benzyl hexyl hexyl hexyl hexyl isobutyl isobutyl isobutyl isobutyl 4-MeO-benzyl 4-MeO-benzyl 4-MeO-benzyl 4-MeO-benzyl benzyl benzyl benzyl benzyl hexyl hexyl hexyl hexyl isobutyl isobutyl isobutyl isobutyl 4-MeO-benzyl 4-MeO-benzyl 4-MeO-benzyl 4-MeO-benzyl benzyl benzyl benzyl benzyl hexyl hexyl hexyl hexyl isobutyl isobutyl isobutyl isobutyl 4-MeO-benzyl 4-MeO-benzyl 4-MeO-benzyl 4-MeO-benzyl

isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl

92 69 59 67 64 82 68 59 81 70 65 59 70 70 60 50 82 77 79 85 97 89 72 83 84 85 92 63 63 65 92 64 55 99 71 94 68 94 87 91 84 95 99 99 94 92 80 89

>98 95 >98 68 >98 87 >98 54 >98 >98 >98 84 >98 >98 >98 54 >98 >98 >98 >98 >98 >98 >98 >98 >98 >98 >98 >98 >98 >98 >98 81 >98 95 >98 88 >98 >98 >98 91 >98 >98 87 >98 >98 >98 >98 80

80:20 >90:10 83:17 ND 92:8 96:4 92:8 ND 84:16 >95:5 83:17 ND 81:19 89:11 82:18 ND 94:6 >98:2 87:13 >95:5 84:16 94:6 97:3 88:12 83:17 >98:2 87:13 >95:5 94:6 96:4 94:6 >95:5 79:21 >95:5 85:15 99:1 >98:2 96:4 89:11 ND 89:11 >98:2 78:22 ND 81:19 94:6 86:14 ND

a Based on mass recovery of the crude product after cleavage from the PS-DES resin. b Determined by LCMS. c Determined by 1H NMR.

Library Synthesis. Parallel solid-phase synthesis of the 1,3-oxazolidine libraries was initiated by the coupling of each enantiomer of the trans 3-phenylglycidol derivatives (2S,3S)1A-C and (2R,3R)-2A-C onto the PS-DES resin in its chlorinated form (Scheme 1).39 The direct attachment of (2S,3S)-1A-C and (2R,3R)-2A-C can also be achieved via Wilkinson’s catalyst mediated alcoholysis of the polymerbound trialkylsilane.40 However, the purities of the final oxazolidine compounds (isolated after cleavage from the resin) were higher using the former procedure. The derivatization of the PS-DES resin with the oxirane was monitored by gel-phase 13C NMR according to the procedure described by Lorge´ and co-workers41 and typically proceeded in up to 97% completion. The regio- and stereoselective opening of these polymerbound oxiranes was then performed in parallel by heating

the resin-supported glycidols at 70 °C in the presence of the amines (3a-d) in ethanol. Subsequent condensation of the polymer-bound β-amino alcohols with aliphatic aldehydes (4a-d) using MgSO4 in benzene (60 °C) led to the 1,3oxazolidines, confirmed by the presence of the characteristic signal of C-2 at ca. 99 ppm in the gel-phase 13C NMR spectrum. The cleavage of the PS-DES-supported 1,3-oxazolidines was performed with TBAF in THF at room temperature. Although the reaction with pyridine-HF complex was also successful, the lability of some library members toward acidic aqueous medium prompted the choice of the fluoridemediated cleavage for the whole library. At this stage all the library members (5Aaa-Cdd and 6Aaa-Cdd) were characterized in their crude forms by 1H NMR and by liquidchromatography coupled to a mass spectrometer (LCMS).

Synthesis and Characterization of a 1,3-Oxazolidine Library

Journal of Combinatorial Chemistry, 2000, Vol. 2, No. 6 701

Table 2. Characterization of the (2S,4S,5S)-1,3-Oxazolidine Library 6Aaa-Cdd entry

R1

R2

R3

yielda/%

purityb/%

ratioc 2S:2R

6Aaa 6Aab 6Aac 6Aad 6Aba 6Abb 6Abc 6Abd 6Aca 6Acb 6Acc 6Acd 6Ada 6Adb 6Adc 6Add 6Baa 6Bab 6Bac 6Bad 6Bba 6Bbb 6Bbc 6Bbd 6Bca 6Bcb 6Bcc 6Bcd 6Bda 6Bdb 6Bdc 6Bdd 6Caa 6Cab 6Cac 6Cad 6Cba 6Cbb 6Cbc 6Cbd 6Cca 6Ccb 6Ccc 6Ccd 6Cda 6Cdb 6Cdc 6Cdd

H H H H H H H H H H H H H H H H NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 NO2 Br Br Br Br Br Br Br Br Br Br Br Br Br Br Br Br

benzyl benzyl benzyl benzyl hexyl hexyl hexyl hexyl isobutyl isobutyl isobutyl isobutyl 4-MeO-benzyl 4-MeO-benzyl 4-MeO-benzyl 4-MeO-benzyl benzyl benzyl benzyl benzyl hexyl hexyl hexyl hexyl isobutyl isobutyl isobutyl isobutyl 4-MeO-benzyl 4-MeO-benzyl 4-MeO-benzyl 4-MeO-benzyl benzyl benzyl benzyl benzyl hexyl hexyl hexyl hexyl isobutyl isobutyl isobutyl isobutyl 4-MeO-benzyl 4-MeO-benzyl 4-MeO-benzyl 4-MeO-benzyl

isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl isopropyl hexyl cyclohexyl 2,2,4-(Me)3-pentyl

51 64 55 55 55 59 64 51 71 65 69 69 62 54 73 61 66 78 70 65 75 97 63 74 74 82 72 87 74 79 74 72 70 74 75 90 94 80 76 77 67 81 74 78 71 90 75 78

>98 95 >98 91 >98 90 >98 29 >98 >98 >98 >85 >98 >98 >98 >90 >98 >98 >98 >98 >98 >95 >98 >95 >98 >98 >98 >98 81 94 93 >90 >98 >95 >98 >98 >95 >95 >98 >90 >98 >98 >98 >98 >98 >98 >98 >98

85:15 >9:1 84:16 >95:5 >95:5 94:6 94:6 ND 91:9 92:8 89:11 ND 81:19 95:5 83:17 >95:5 9:1 96:4 9:1 93:7 9:1 98:2 96:4 98:2 79:11 >98:2 84:16 98:2 92:8 95:5 9:1 >95:5 78:22 93:7 84:16 ND 91:9 95:5 89:11 ND 87:13 94:6 86:14 98:2 84:16 94:6 82:18 ND

a Based on mass recovery of the crude product after cleavage from the PS-DES resin. b Determined by LCMS. c Determined by 1H NMR.

In addition, the 5Aaa-Cdd sub-library was also characterized by 13C NMR. This facile and concise route generates the 1,3-oxazolidines in good yields(2R,4R 5R)-5Aaa-Cdd 50-99% (mean yield 78%); (2S,4S,5S)-6Aaa-Cdd 51-97% (mean yield 71.4%)s and excellent purity following the cleavage step (determined by 1H, 13C NMR, and LCMS) (see Tables 1 and 2). The branched aldehyde 4d was the only building block that caused any problems during library construction, reflected in purities of 98% (rt: 2.06 min). 5Aab: 1H NMR (CDCl3): 0.89 (t, J ) 7.1 Hz, 3H, CH3), 1.0-1.6 (m, 10H, CH2 of hexyl), 3.11 (dd, J1 ) 11.6 Hz and J2 ) 4.4 Hz, 1H, 1H of CH2O), 3.31 (dd, J1 ) 11.6 Hz and J2 ) 7.2 Hz, 1H, 1H of CH2O), 3.53 and 3.89 (2d, J ) 14.1 Hz, 2H, NCH2Ph), 4.02 (d, J ) 7.9 Hz, 1H, H4), 4.18 (td, J1 ) 7.8 Hz, J2 ) 7.2 Hz, J3 ) 4.4 Hz, 1H, H5), 4.27 (dd, J1 ) 7.1 Hz and J2 ) 2.1 Hz, 1H, H2), 7.1-7.4 (m, 10 H, Ar). 13C NMR (CDCl3): 14.1, 22.6, 24.0, 29.3, 31.8, 34.1, 54.3, 63.4, 68.6, 79.0, 95.8, 127.1, 127.8, 128.0 (2C), 128.2 (2C), 128.5 (2C), 129.2 (3C), 137.0. MS: Calcd for C23H32NO2 [M + H]+: 354.3. Found: 354.3. Purity LCMS: 95% (rt: 2.25 min). 5Aac: 1H NMR (CDCl3): 0.97 (m, 2H, 4-CH2 of cyclohexyl), 1.0-1.9 (m, 8H, CH2 of cyclohexyl), 1.95 (m, 1H, CH of cyclohexyl), 3.06 (dd, J1 ) 11.6 Hz and J2 ) 4.4 Hz,

Tremblay et al.

1H, 1H of CH2O), 3.31 (dd, J1 ) 11.6 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.52 and 3.87 (2d, J ) 14.0 Hz, 2H, NCH2Ph), 3.99 (d, J ) 8.1 Hz, 1H, H4), 4.12 (d, J ) 4.4 Hz, 1H, H2), 4.16 (td, J1 ) 8.1 Hz, J2 ) 7.7 Hz, J3 ) 4.4 Hz, 1H, H5), 7.0-7.4 (m, 10 H, Ar). 13C NMR (CDCl3): 25.3, 26.0, 26.7, 26.9, 29.8, 40.0, 54.4, 63.3, 68.3, 78.6, 99.0, 127.1, 127.7, 128.0 (2C), 128.1 (2C), 128.2 (2C), 129.2 (2C), 129.5, 137.0. MS: Calcd for C23H30NO2 [M + H]+: 352.2. Found: 352.3. Purity LCMS: >98% (rt: 2.26 min). 5Aba: 1H NMR (CDCl3): 0.80 (t, J ) 7.1 Hz, 3H, CH3 of hexyl), 1.0-1.3 (m, 14H, CH2 of hexyl and CH3 of isopropyl), 1.90 (m, 1H, CH(CH3)2), 2.50 (m, 2H, CH2N), 3.04 (dd, J1 ) 11.6 Hz and J2 ) 4.4 Hz, 1H, 1H of CH2O), 3.25 (dd, J1 ) 11.4 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.97 (d, J ) 8.3 Hz, 1H, H4), 4.09 (d, J ) 2.6 Hz, 1H, H2), 4.20 (td, J1 ) 8.3 Hz, J2 ) 7.7 Hz, J3 ) 4.4 Hz, 1H, H5), 7.1-7.4 (m, 5H, Ar). 13C NMR (CDCl3): 14.0, 14.9, 19.2, 22.5, 27.2, 27.8, 30.7, 31.5, 51.6, 63.4, 69.6, 79.1, 99.6, 127.5, 128.1 (2C), 128.2 (2C), 138.9. MS: Calcd for C19H32NO2 [M + H]+: 306.2. Found: 306.3. Purity LCMS: >98% (rt: 1.80 min). 5Abb: 1H NMR (CDCl3): 0.81 (t, J ) 7.0 Hz, 3H, CH3 of hexyl), 0.91 (t, J ) 7.0 Hz, 3H, CH3 of hexyl), 1.0-1.8 (m, 18H, CH2 of hexyl), 2.52 (m, 2H, CH2N), 3.10 (dd, J1 ) 11.7 Hz and J2 ) 4.4 Hz, 1H, 1H of CH2O), 3.21 (dd, J1 ) 11.7 Hz and J2 ) 7.3 Hz, 1H, 1H of CH2O), 3.93 (d, J ) 7.7 Hz, 1H, H4), 4.20 (m, 2H, H5 and H2), 7.2-7.4 (m, 5H, Ar). 13C NMR (CDCl3): 14.0, 14.1, 22.5, 22.7, 24.5, 27.1, 28.1, 29.5, 31.5, 31.9, 34.8, 51.7, 63.3, 69.4, 79.7, 96.3, 127.5, 128.0 (2C), 128.2 (2C), 139.1. MS: Calcd for C22H38NO2 [M + H]+: 348.3. Found: 348.3. Purity LCMS: 87% (rt: 1.88 min). 5Abc: 1H NMR (CDCl3): 0.80 (m, 5H, CH3 of hexyl and 4-CH2 of cyclohexyl), 1.0-1.9 (m, 16H, CH2 of hexyl and CH2 of cyclohexyl), 2.05 (m, 1H, CH of cyclohexyl), 2.50 (m, 2H, CH2N), 3.06 (dd, J1 ) 11.6 Hz and J2 ) 4.4 Hz, 1H, 1H of CH2O), 3.22 (dd, J1 ) 11.7 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.94 (d, J ) 8.3 Hz, 1H, H4), 4.05 (d, J ) 2.8 Hz, 1H, H2), 4.17 (td, J1 ) 8.3 Hz, J2 ) 7.7 Hz, J3 ) 4.4 Hz, 1H, H5), 7.3-7.4 (m, 5H, Ar). 13C NMR (CDCl3): 14.0, 22.5, 25.7, 26.2, 26.8, 26.9, 27.1, 27.8, 29.9, 31.5, 41.0, 51.7, 63.4, 69.4, 79.3, 99.4, 127.5, 128.1 (2C), 128.1 (2C), 139.1. MS: Calcd for C22H36NO2 [M + H]+: 346.3. Found: 346.3. Purity LCMS: >98% (rt: 1.99 min). 5Aca: 1H NMR (CDCl3): 0.71 and 0.76 (2d, J ) 6.6 and 6.2 Hz, 6H, 2 × CH3 of isobutyl), 1.08 and 1.11 (2d, J ) 6.8 Hz, 6H, 2 × CH3 of isopropyl), 1.43 (m, 1H, CH(CH3)2), 1.94 (m, 1H, CH(CH3)2), 2.23 (dd, J1 ) 12.5 Hz and J2 ) 9.1 Hz, 1H, 1H of CH2N), 2.35 (dd, J1 ) 12.5 Hz and J2 ) 5.9 Hz, 1H, 1H of CH2N), 3.07 (dd, J1 ) 11.5 Hz and J2 ) 4.4 Hz, 1H, 1H of CH2O), 3.24 (dd, J1 ) 11.5 Hz and J2 ) 7.9 Hz, 1H, 1H of CH2O), 3.83 (d, J ) 8.1 Hz, 1H, H4), 4.00 (d, J ) 2.8 Hz, 1H, H2), 4.20 (td, J1 ) 8.1 Hz, J2 ) 7.9 Hz, J3 ) 4.4 Hz, 1H, H5), 7.3-7.5 (m, 5H, Ar);13C NMR (CDCl3): 15.3, 19.4, 20.2, 20.8, 21.2, 27.5, 31.0, 62.5, 63.3, 71.2, 79.51, 100.8, 127.4, 128.2 (2C), 129.3, 139.8. MS: Calcd for C17H28NO2 [M + H]+: 278.2. Found: 278.2. Purity LCMS: >98% (rt: 1.98 min).

Synthesis and Characterization of a 1,3-Oxazolidine Library

5Acb: 1H NMR (CDCl3): 0.71 and 0.79 (2d, J ) 6.6 and 6.2 Hz, 6H, 2 × CH3 of isobutyl), 0.91 (m, 3H, CH3 of hexyl), 1.0-1.6 (m, 10H, CH2 of hexyl), 1.75 (m, 1H, CH(CH3)2), 2.22 (dd, J1 ) 12.5 Hz and J2 ) 9.1 Hz, 1H, 1H of CH2N), 2.38 (dd, J1 ) 12.5 Hz and J2 ) 5.9 Hz, 1H, 1H of CH2N), 3.13 (dd, J1 ) 11.5 Hz and J2 ) 4.4 Hz, 1H, 1H of CH2O), 3.21 (dd, J1 ) 11.5 Hz and J2 ) 7.9 Hz, 1H, 1H of CH2O), 3.83 (d, J ) 7.7 Hz, 1H, H4), 4.13 (d, J ) 2.2 Hz, 1H, H2), 4.19 (m, 1H, H5), 7.3-7.5 (m, 5H, Ar). 13 C NMR (CDCl3): 14.1, 20.8, 22.5, 24.8, 27.6, 28.8, 29.6, 31.9, 35.1, 62.0, 63.2, 70.8, 80.0, 97.2, 127.4, 128.0 (2C), 128.1 (2C), 139.75. MS: Calcd for C20H34NO2 [M + H]+: 320.3. Found: 320.3. Purity LCMS: >98% (rt: 2.13 min). 5Acc: 1H NMR (CDCl3): 0.71 and 0.76 (2d, J ) 6.6 and 6.2 Hz, 6H, 2 × CH3 of isobutyl), 1.0-1.9 (m, 11H, CH2 of cyclohexyl and CH(CH3)2), 2.13 (m, 1H, CH of cyclohexyl), 2.24 (dd, J1 ) 12.5 Hz and J2 ) 9.1 Hz, 1H, 1H of CH2N), 2.36 (dd, J1 ) 12.5 Hz and J2 ) 5.9 Hz, 1H, 1H of CH2N), 3.07 (dd, J1 ) 11.6 Hz and J2 ) 4.1 Hz, 1H, 1H of CH2O), 3.23 (dd, J1 ) 11.7 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.81 (d, J ) 8.1 Hz, 1H, H4), 3.98 (d, J ) 2.9 Hz, H2), 4.18 (td, J1 ) 8.1 Hz, J2 ) 7.7 Hz, J3 ) 4.4 Hz, 1H, H5), 7.3-7.5 (m, 5H, Ar). 13C NMR (CDCl3): 20.8, 21.2, 26.0, 26.3, 26.7, 26.8, 27.6, 30.0, 41.2, 62.6, 63.3, 71.0, 79.6, 100.5, 127.4, 128.0 (2C), 128.1 (2C), 140.0. MS: Calcd for C20H32NO2 [M + H]+: 318.2. Found: 318.3. Purity LCMS: >98% (rt: 2.18 min). 5Ada: 1H NMR (CDCl3): 0.95 and 1.01 (2d, J ) 6.8 Hz, 6H, 2 × CH3 of isopropyl), 1.75 (m, 1H, CH(CH3)2), 3.05 (dd, J1 ) 11.7 Hz and J2 ) 4.4 Hz, 1H, 1H of CH2O), 3.33 (dd, J1 ) 11.7 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.51 (d, J ) 14.3 Hz, 1H, 1H of ArCH2N), 3.78 (m, 4H, CH3O and 1H of ArCH2N), 4.01 (d, J ) 8.1 Hz, 1H, H4), 4.14 (m, 2H, H5 and H2), 6.76 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.02 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.35 (m, 5H, Ar). 13C NMR (CDCl ): 14.4, 19.1, 29.5, 53.0, 55.2, 63.4, 67.9, 3 78.4, 98.6, 113.4 (2C), 127.7, 128.3 (2C), 128.5 (2C), 128.6, 130.4 (2C), 136.8, 158.7. MS: Calcd for C21H28NO3 [M + H]+: 342.2. Found: 342.2. Purity LCMS: >98% (rt: 1.92 min). 5Adb: 1H NMR (CDCl3): 0.88 (t, J ) 7.0 Hz, 3H, CH3 of hexyl), 1.0-1.7 (m, 10H, CH2 of hexyl), 3.10 (dd, J1 ) 11.4 Hz and J2 ) 4.4 Hz, 1H, 1H of CH2O), 3.30 (dd, J1 ) 11.7 Hz and J2 ) 7.0 Hz, 1H, 1H of CH2O), 3.49 (d, J ) 14.1 Hz, 1H, 1H of ArCH2N), 3.81 (m, 4H, CH3O and 1H of ArCH2N), 4.01 (d, J ) 7.6 Hz, 1H, H4), 4.15 (ABX system, 1H, H5), 4.25 (dd, J1 ) 6.0 Hz and J2 ) 2.0 Hz, 1H, H2), 6.78 (d, J ) 8.6 Hz, 2H, 2 × CH of Ar), 7.04 (d, J ) 8.6 Hz, 2H, 2 × CH of Ar), 7.3-7.4 (m, 5H, Ar). 13C NMR (CDCl3): 14.1, 22.6, 24.0, 29.3, 31.8, 34.0, 53.1, 55.2, 63.4, 68.1, 78.9, 95.3, 113.4 (2C), 127.7, 128.2 (2C), 128.5 (2C), 128.8, 130.4 (2C), 137.0, 158.7. MS: Calcd for C24H34NO3 [M + H]+: 384.3. Found: 384.3. Purity LCMS: >98% (rt: 2.02 min). 5Adc: 1H NMR (CDCl3): 1.00 (m, 2H, 4-CH2 of cyclohexyl), 1.1-1.8 (m, 8H, CH2 of cyclohexyl), 1.96 (m, 1H, CH of cyclohexyl), 3.04 (dd, J1 ) 11.4 Hz and J2 ) 4.4 Hz, 1H, 1H of CH2O), 3.32 (dd, J1 ) 11.4 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.50 (d, J ) 13.9 Hz, 1H, 1H of ArCH2N),

Journal of Combinatorial Chemistry, 2000, Vol. 2, No. 6 705

3.80 (m, 4H, CH3O and 1H of ArCH2N), 3.97 (d, J ) 7.6 Hz, 1H, H4), 4.11 (m, 2H, H5 and H2), 6.77 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.03 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.3-7.4 (m, 5H, Ar). 13C NMR (CDCl3): 25.3, 26.1, 26.7, 26.9, 29.8, 39.9, 53.2, 55.3, 63.4, 67.8, 78.6, 98.5, 113.4 (2C), 127.7, 128.2 (2C), 128.4 (2C), 128.7 (2C), 129.4, 130.4 (2C), 137.0, 158.8. MS: Calcd for C24H32NO3 [M + H]+: 382.2. Found: 382.3. Purity LCMS: >98% (rt: 2.12 min). 5Baa: 1H NMR (CDCl3): 1.07 and 1.08 (2d, J ) 6.9 Hz, 6H, 2 × CH3), 1.90 (m, 1H, CH(CH3)2), 3.02 (dd, J1 ) 11.6 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.23 (dd, J1 ) 11.6 Hz and J2 ) 7.5 Hz, 1H, 1H of CH2O), 3.68 and 3.77 (2d, J ) 13.8 Hz, 2H, NCH2Ph), 4.07 (d, J ) 8.2 Hz, 1H, H4), 4.21 (d, J ) 2.7 Hz, 1H, H2), 4.23 (ABX system, 1H, H5), 7.0-7.3 (m, 5H, Ar), 7.42 (d, J ) 8.8 Hz, 2H, 2 × CH2 of ArNO2), 8.06 (d, J ) 8.8 Hz, 2H, 2 × CH2 of ArNO2). 13C NMR (CDCl3): 14.5, 19.1, 30.0, 55.4, 62.9, 68.1, 78.9, 99.2, 123.2 (2C), 127.4, 128.1 (2C), 128.3 (2C), 129.2 (2C), 136.5, 146.4, 147.2. MS: Calcd for C20H25N2O4 [M + H]+: 357.2. Found: 357.2. Purity LCMS: >98% (rt: 2.10 min). 5Bab: 1H NMR (CDCl3): 0.88 (m, 3H, CH3 of hexyl), 1.1-1.8 (m, 10H, CH2 of hexyl), 3.07 (dd, J1 ) 11.6 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.20 (dd, J1 ) 11.7 Hz and J2 ) 7.3 Hz, 1H, 1H of CH2O), 3.73 (s, 2H, PhCH2N), 4.06 (d, J ) 8.1 Hz, 1H, H4), 4.25 (ABX system, 1H, H5), 4.35 (dd, J1 ) 6.6 Hz and J2 ) 2.2 Hz, 1H, H2), 7.0-7.2 (m, 5H, Ar), 7.44 (d, J ) 8.6 Hz, 2H, 2 × CH2 of ArNO2), 8.08 (d, J ) 8.6 Hz, 2H, 2 × CH2 of ArNO2). 13C NMR (CDCl3): 14.1, 22.6, 24.3, 29.3, 31.8, 34.0, 55.4, 62.8, 68.0, 79.3, 96.0, 123.2 (2C), 127.4, 128.1 (3C), 129.0 (3C), 136.8, 146.5, 147.2. MS: Calcd for C23H31N2O4 [M + H]+: 399.2. Found: 399.3. Purity LCMS: >98% (rt: 2.35 min). 5Bac: 1H NMR (CDCl3): 0.92 (m, 2H, 4-CH2 of cyclohexyl), 1.1-1.9 (m, 8H, CH2 of cyclohexyl), 2.05 (m, 1H, CH of cyclohexyl), 3.02 (dd, J1 ) 11.5 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.22 (dd, J1 ) 11.6 Hz and J2 ) 7.6 Hz, 1H, 1H of CH2O), 3.70 and 3.75 (2d, J ) 13.6 Hz, 2H, PhCH2N), 4.03 (d, J ) 8.1 Hz, 1H, H4), 4.19 (d, J ) 2.6 Hz, 1H, H2), 4.23 (td, J1 ) 8.0 Hz, J2 ) 7.6 Hz, J3 ) 4.0 Hz, 1H, H5), 7.0-7.2 (m, 5H, Ar), 7.42 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2), 8.08 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2). 13C NMR (CDCl3): 25.8, 26.0, 26.6, 26.7, 29.8, 40.3, 55.7, 62.8, 68.0, 79.0, 99.2, 123.2 (2C), 127.4, 128.0 (2C), 128.2 (2C), 129.1 (2C), 136.7, 146.6, 147.2. MS: Calcd for C23H29N2O4 [M + H]+: 397.2. Found: 397.2. Purity LCMS: >98% (rt: 2.27 min). 5Bba: 1H NMR (CDCl3): 0.78 (t, J ) 6.8 Hz, 3H, CH3 of hexyl), 1.0-1.5 (m, 14H, CH2 of hexyl and 2 × CH3 of isopropyl), 1.96 (m, 1H, CH(CH3)2), 2.55 (2m, 2H, CH2N), 3.05 (dd, J1 ) 11.6 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.16 (dd, J1 ) 11.4 Hz and J2 ) 7.6 Hz, 1H, 1H of CH2O), 4.03 (d, J ) 8.5 Hz, 1H, H4), 4.09 (d, J ) 2.9 Hz, 1H, H2), 4.25 (td, J1 ) 8.0 Hz, J2 ) 7.6 Hz, J3 ) 4.0 Hz, 1H, H5), 7.56 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2), 8.16 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2). 13C NMR (CDCl3): 13.9, 15.2, 19.1, 22.5, 27.0, 28.4, 30.7, 31.4, 52.3, 62.9, 69.0, 79.2, 99.7, 123.3 (2C), 128.9 (2C), 147.3, 148.2. MS: Calcd for C19H31N2O4 [M + H]+: 351.2. Found: 351.3. Purity LCMS: >98% (rt: 2.30 min).

706 Journal of Combinatorial Chemistry, 2000, Vol. 2, No. 6

5Bbb: 1H NMR (CDCl3): 0.79 (t, J ) 7.0 Hz, 3H, CH3 of hexyl), 0.91 (m, 3H, CH3 of hexyl), 1.1-1.9 (m, 18H, CH2 of both hexyl groups), 2.55 (m, 2H, CH2N), 3.14 (ABX system, 2H, CH2O), 3.99 (d, J ) 8.0 Hz, 1H, H4), 4.23 (m, 2H, H5 and H2), 7.53 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2), 8.15 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2). 13C NMR (CDCl3): 13.9, 14.1, 22.4, 22.6, 24.6, 26.9, 28.6, 29.5, 31.4, 31.8, 34.4, 52.2, 62.8, 68.7, 79.8, 96.4, 123.2 (2C), 128.8 (2C), 147.3, 148.3. MS: Calcd for C22H37N2O4 [M + H]+: 393.3. Found: 393.3. Purity LCMS: >98% (rt: 2.50 min). 5Bbc: 1H NMR (CDCl3): 0.79 (t, J ) 7.0 Hz, 3H, CH3 of hexyl), 1.0-1.9 (m, 18H, CH2 of cyclohexyl), 2.05 (m, 1H, CH of cyclohexyl), 2.50 and 2.57 (2m, 2H, CH2N), 3.06 (dd, J1 ) 11.6 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.15 (dd, J1 ) 11.7 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.99 (d, J ) 8.1 Hz, 1H, H4), 4.05 (d, J ) 2.9 Hz, 1H, H2), 4.23 (ABX system, 1H, H5), 7.55 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2), 8.16 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2). 13C NMR (CDCl3): 13.9, 22.5, 26.0, 26.1, 26.6, 26.7, 27.0, 28.4, 29.8, 31.4, 40.9, 52.4, 62.8, 68.9, 79.4, 99.5, 123.2 (2C), 128.9 (2C), 147.3, 148.4. MS: Calcd for C22H35N2O4 [M + H]+: 391.3. Found: 391.3. Purity LCMS: >98% (rt: 2.50 min). 5Bca: 1H NMR (CDCl3): 0.68 and 0.76 (2d, J ) 6.6 and 6.2 Hz, 6H, 2 × CH3 of isobutyl), 1.09 and 1.12 (2d, J ) 6.8 Hz, 6H, 2 × CH3 of isopropyl), 1.37 (m, 1H, CH(CH3)2), 1.96 (m, 1H, CH(CH3)2), 2.28 (dd, J1 ) 12.5 Hz and J2 ) 9.9 Hz, 1H, 1H of CH2N), 2.40 (dd, J1 ) 12.5 Hz and J2 ) 4.8 Hz, 1H, 1H of CH2N), 3.08 (dd, J1 ) 11.5 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.19 (dd, J1 ) 11.5 Hz and J2 ) 7.9 Hz, 1H, 1H of CH2O), 3.91 (d, J ) 8.1 Hz, 1H, H4), 4.00 (d, J ) 3.3 Hz, 1H, H2), 4.25 (td, J1 ) 8.1 Hz, J2 ) 7.9 Hz, J3 ) 4.0 Hz, 1H, H5), 7.56 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2), 8.15 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2);13C NMR (CDCl3): 15.6, 19.3, 20.5, 21.1, 27.8, 31.0, 62.6 (2C), 70.4, 79.4, 100.7, 123.2 (2C), 128.8 (2C), 147.3, 148.7. MS: Calcd for C17H27N2O4 [M + H]+: 323.2. Found: 323.2. Purity LCMS: >98% (rt: 2.13 min). 5Bcb: 1H NMR (CDCl3): 0.66 and 0.77 (2d, J ) 6.6 and 6.2 Hz, 6H, 2 × CH3 of isobutyl), 0.91 (m, 3H, CH3 of hexyl), 1.2-1.8 (m, 11H, CH2 of hexyl and CH(CH3)2), 2.26 (dd, J1 ) 12.5 Hz and J2 ) 9.5 Hz, 1H, 1H of CH2N), 2.43 (dd, J1 ) 12.5 Hz and J2 ) 5.1 Hz, 1H, 1H of CH2N), 3.12 (ABX system, 2H, CH2O), 3.91 (d, J ) 7.7 Hz, 1H, H4), 4.19 (dd, J1 ) 7.3 Hz and J2 ) 2.6 Hz, 1H, H2), 4.24 (td, J1 ) 7.8 Hz, J2 ) 7.7 Hz, J3 ) 4.4 Hz, 1H, H5), 7.53 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2), 8.15 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2). 13C NMR (CDCl3): 14.1, 20.5, 20.9, 22.6, 24.9, 27.8, 29.5, 31.9, 34.7, 62.1, 62.6, 69.9, 80.1, 97.1, 123.2 (2C), 128.8 (2C), 147.3, 148.7. MS: Calcd for C20H33N2O4 [M + H]+: 365.2. Found: 365.2. Purity LCMS: >98% (rt: 2.44 min). 5Bcc: 1H NMR (CDCl3): 0.68 and 0.76 (2d, J ) 6.8 and 6.6 Hz, 6H, 2 × CH3 of isobutyl), 0.8-1.9 (m, 11H, CH2 of cyclohexyl and CH(CH3)2), 2.05 (m, 1H, CH of cyclohexyl), 2.29 (dd, J1 ) 12.5 Hz and J2 ) 9.9 Hz, 1H, 1H of CH2N), 2.40 (dd, J1 ) 12.5 Hz and J2 ) 5.0 Hz, 1H, 1H of CH2N), 3.08 (dd, J1 ) 11.6 Hz and J2 ) 4.1 Hz, 1H, 1H of CH2O),

Tremblay et al.

3.16 (dd, J1 ) 11.6 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.89 (d, J ) 8.1 Hz, 1H, H4), 4.01 (d, J ) 3.3 Hz, 1H, H2), 4.23 (td, J1 ) 8.0 Hz, J2 ) 7.7 Hz, J3 ) 4.1 Hz, 1H, H5), 7.55 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2), 8.15 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2). 13C NMR (CDCl3): 20.5, 21.1, 26.2, 26.3, 26.6, 26.7, 27.8, 29.9, 41.1, 62.7 (2C), 70.2, 79.7, 100.4, 123.2 (2C), 128.9 (2C), 147.3, 148.8. MS: Calcd for C20H31N2O4 [M + H]+: 363.2. Found: 363.3. Purity LCMS: >98% (rt: 2.35 min). 5Bda: 1H NMR (CDCl3): 1.06 and 1.08 (2d, J ) 7.0 and 6.6 Hz, 6H, 2 × CH3 of isopropyl), 1.93 (m, 1H, CH(CH3)2), 3.01 (dd, J1 ) 11.6 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.22 (dd, J1 ) 11.6 Hz and J2 ) 7.6 Hz, 1H, 1H of CH2O), 3.66 and 3.77 (2d, J ) 18 Hz, 2H, ArCH2N), 3.72 (s, 3H, CH3O), 4.05 (d, J ) 8.4 Hz, 1H, H4), 4.22 (m, 2H, H5 and H2), 6.68 (d, J ) 8.8 Hz, 2H, 2 × CH of ArOMe), 6.95 (d, J ) 8.8 Hz, 2H, 2 × CH of ArOMe), 7.43 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2), 8.09 (d, J ) 8.8 Hz, 2H, 2 × CH of ArNO2). 13C NMR (CDCl3): 14.9, 19.1, 29.9, 54.4, 55.2, 62.9, 67.7, 78.7, 99.0, 113.4 (2C), 123.2 (2C), 128.4, 129.2 (2C), 129.9 (2C), 146.4, 147.2, 158.9. MS: Calcd for C21H27N2O5 [M + H]+: 387.2. Found: 387.2. Purity LCMS: >98% (rt: 2.05 min). 5Bdb: 1H NMR (CDCl3): 0.90 (t, J ) 7.2 Hz, 3H, CH3 of hexyl), 1.1-1.8 (m, 10H, CH2 of hexyl), 3.06 (dd, J1 ) 11.6 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.19 (dd, J1 ) 11.6 Hz and J2 ) 7.3 Hz, 1H, 1H of CH2O), 3.73 (s, 3H, CH3O), 3.78 (m, 2H, ArCH2N), 4.05 (d, J ) 8.1 Hz, 1H, H4), 4.23 (ABX system, 1H, H4), 4.33 (dd, J1 ) 6.4 Hz and J2 ) 2.2 Hz, 1H, H2), 6.69 (d, J ) 8.5 Hz, 2H, 2 × CH of ArOMe), 6.97 (d, J ) 8.5 Hz, 2H, 2 × CH of ArOMe), 7.44 (d, J ) 8.7 Hz, 2H, 2 × CH of ArNO2), 8.09 (d, J ) 8.7 Hz, 2H, 2 × CH of ArNO2). 13C NMR (CDCl3): 14.1, 22.6, 24.3, 29.4, 31.8, 33.9, 54.4, 55.2, 62.9, 67.7, 79.2, 95.7, 113.5 (2C), 123.2 (2C), 128.7, 129.0 (2C), 130.3 (2C), 146.5, 147.2, 158.9. MS: Calcd for C24H33N2O5 [M + H]+: 429.2. Found: 429.3. Purity LCMS: >98% (rt: 2.29 min). 5Bdc: 1H NMR (CDCl3): 0.94 (m, 2H, 4-CH2 of cyclohexyl), 1.0-1.9 (m, 8H, CH2 of cyclohexyl), 2.05 (m, 1H, CH of cyclohexyl), 3.02 (dd, J1 ) 11.7 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.21 (dd, J1 ) 11.7 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.72 (s, 3H, CH3O), 3.78 (m, 2H, ArCH2N), 4.02 (d, J ) 8.4 Hz, 1H, H4), 4.17 (d, J ) 2.9 Hz, 1H, H2), 4.21 (td, J1 ) 8.2 Hz, J2 ) 7.8 Hz, J3 ) 4.0 Hz, 1H, H5), 6.67 (d, J ) 8.6 Hz, 2H, 2 × CH of ArOMe), 6.95 (d, J ) 8.6 Hz, 2H, 2 × CH of ArOMe), 7.42 (d, J ) 8.6 Hz, 2H, 2 × CH of ArNO2), 8.09 (d, J ) 8.6 Hz, 2H, 2 × CH of ArNO2). 13C NMR (CDCl3): 13.7, 20.3, 25.7, 26.1, 26.7, 29.7, 30.3, 40.2, 54.6, 55.2, 62.8, 67.6, 78.9, 98.9, 113.4 (2C), 123.1 (2C), 128.5, 129.0 (2C), 130.3 (2C), 146.6, 147.1, 158.9. MS: Calcd for C24H31N2O5 [M + H]+: 427.2. Found: 427.2. Purity LCMS: >98% (rt: 2.25 min). 5Caa: 1H NMR (CDCl3): 0.98 and 1.02 (2d, J ) 6.9 Hz, 6H, 2 × CH3), 1.80 (m, 1H, CH(CH3)2), 3.03 (dd, J1 ) 11.7 Hz and J2 ) 4.4 Hz, 1H, 1H of CH2O), 3.29 (dd, J1 ) 11.7 Hz and J2 ) 7.9 Hz, 1H, 1H of CH2O), 3.61 and 3.77 (2d, J ) 14 Hz, 2H, NCH2Ph), 3.96 (d, J ) 8.1 Hz, 1H, H4), 4.15 (m, 2H, H5 and H2), 7.08 (dd, J1 ) 7.0 Hz and J2 ) 2.4 Hz, 2H, 2 × CH of Ar), 7.21 (m, 5H, CH of Ar), 7.41

Synthesis and Characterization of a 1,3-Oxazolidine Library

(d, J ) 8.4 Hz, 2H, 2 × CH of Ar). 13C NMR (CDCl3): 14.6, 19.1, 29.7, 54.4, 63.2, 67.7, 78.4, 99.0, 121.4, 127.2, 128.2 (2C), 129.2 (2C), 130.0 (2C), 131.3 (2C), 136.6 (2C). MS: Calcd for C20H25BrNO2 [M + H]+: 390.1. Found: 390.1. Purity LCMS: >98% (rt: 2.24 min). 5Cab: 1H NMR (CDCl3): 0.88 (m, 3H, CH3 of hexyl), 1.1-1.7 (m, 10H, CH2 of hexyl), 3.09 (dd, J1 ) 11.7 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.26 (dd, J1 ) 11.7 Hz and J2 ) 7.3 Hz, 1H, 1H of CH2O), 3.58 and 3.81 (2d, J ) 14 Hz, 2H, NCH2Ph), 3.95 (d, J ) 7.7 Hz, 1H, H4), 4.17 (td, J1 ) 7.7 Hz, J2 ) 7.7 Hz, J3 ) 4.0 Hz, 1H, H5), 4.28 (dd, J1 ) 6.6 Hz and J2 ) 2.2 Hz, 1H, H2), 7.12 (dd, J1 ) 7.0 Hz and J2 ) 2.2 Hz, 2H, 2 × CH of Ar), 7.22 (m, 5H, CH of Ar), 7.42 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar). 13C NMR (CDCl3): 14.1, 22.6, 24.1, 29.3, 31.8, 34.0, 54.5, 63.2, 67.9, 79.0, 95.7, 121.4, 127.2, 128.1 (2C), 129.1 (2C), 129.9 (2C), 131.4 (2C), 136.6, 136.9. MS: Calcd for C23H31BrNO2 [M + H]+: 432.2. Found: 390.1. Purity LCMS: 95% (rt: 2.48 min). 5Cac: 1H NMR (CDCl3): 0.93 (m, 2H, 4-CH2 of cyclohexyl), 1.1-1.8 (m, 8H, CH2 of cyclohexyl), 1.95 (m, 1H, CH of cyclohexyl), 3.03 (dd, J1 ) 11.4 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.27 (dd, J1 ) 11.4 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.58 and 3.80 (2d, J ) 13.9 Hz, 2H, PhCH2N), 3.92 (d, J ) 8.1 Hz, 1H, H4), 4.12 (d, J ) 2.2 Hz, 1H, H2), 4.14 (td, ABX system, 1H, H5), 7.09 (dd, J1 ) 6.6 Hz and J2 ) 2.2 Hz, 2H, 2 × CH of Ar), 7.22 (m, 5H, CH of Ar), 7.42 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar). 13C NMR (CDCl3): 25.5, 26.0, 26.7, 29.8, 30.3, 40.1, 54.7, 63.2, 67.7, 78.6, 99.0, 121.4, 127.2, 128.0 (2C), 129.2 (2C), 129.9 (2C), 131.3 (2C), 136.7 (2C). MS: Calcd for C23H29BrNO2 [M + H]+: 430.2. Found: 430.1. Purity LCMS: >98% (rt: 2.43 min). 5Cba: 1H NMR (CDCl3): 0.81 (t, J ) 7.1 Hz, 3H, CH3 of hexyl), 1.0-1.4 (m, 14H, CH2 of hexyl and CH3 of isopropyl), 1.92 (m, 1H, CH(CH3)2), 2.50 (m, 2H, CH2N), 3.03 (dd, J1 ) 11.6 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.20 (dd, J1 ) 11.6 Hz and J2 ) 7.9 Hz, 1H, 1H of CH2O), 3.90 (d, J ) 8.3 Hz, 1H, H4), 4.07 (d, J ) 2.8 Hz, 1H, H2), 4.18 (td, J1 ) 8.1 Hz, J2 ) 7.9 Hz, J3 ) 4.0 Hz, 1H, H5), 7.26 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.42 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar). 13C NMR (CDCl3): 13.9, 15.0, 19.1, 22.5, 27.1, 28.0, 30.6, 31.5, 51.8, 63.3, 69.0, 79.0, 99.6, 121.2, 129.8 (2C), 131.2 (2C), 138.6. MS: Calcd for C19H31BrNO2 [M + H]+: 384.2. Found: 384.2. Purity LCMS: >98% (rt: 2.32 min). 5Cbb: 1H NMR (CDCl3): 0.80 (t, J ) 7.0 Hz, 3H, CH3 of hexyl), 0.91 (t, J ) 7.2 Hz, 3H, CH3 of hexyl), 1.0-1.9 (m, 18H, CH2 of both hexyl groups), 2.51 (m, 2H, CH2N), 3.09 (dd, J1 ) 11.6 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.17 (dd, J1 ) 11.6 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.87 (d, J ) 7.9 Hz, 1H, H4), 4.17 (m, 2H, H5 and H2), 7.22 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.42 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar). 13C NMR (CDCl3): 14.0 (2C) 22.5 (2C), 24.6, 27.0, 28.3, 29.5, 31.5, 31.9, 34.7, 51.9, 63.2, 68.8, 79.6, 96.2, 121.2, 129.7 (2C), 131.2 (2C), 138.8. MS: Calcd for C22H37BrNO2 [M + H]+: 426.2. Found: 426.2. Purity LCMS: >95% (rt: 2.39 min).

Journal of Combinatorial Chemistry, 2000, Vol. 2, No. 6 707

5Cbc: 1H NMR (CDCl3): 0.81 (m, 5H, CH3 of hexyl and 4-CH2 of cyclohexyl), 1.0-1.9 (m, 16H, CH2 of hexyl and CH2 of cyclohexyl), 2.05 (m, 1H, CH of cyclohexyl), 2.50 (m, 2H, CH2N), 3.03 (dd, J1 ) 11.7 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.18 (dd, J1 ) 11.7 Hz and J2 ) 7.9 Hz, 1H, 1H of CH2O), 3.87 (d, J ) 8.1 Hz, 1H, H4), 4.03 (d, J ) 2.6 Hz, 1H, H2), 4.15 (td, J1 ) 8.1 Hz, J2 ) 7.9 Hz, J3 ) 4.0 Hz, 1H, H5), 7.24 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.42 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar). 13C NMR (CDCl3): 14.0, 22.5, 25.8, 26.2, 26.7, 26.8, 27.1, 28.0, 29.8, 31.5, 40.9, 51.9, 63.2, 68.8, 79.2, 99.4, 121.2, 129.8 (2C), 131.2 (2C), 138.8. MS: Calcd for C22H35BrNO2 [M + H]+: 424.2. Found: 424.2. Purity LCMS: >98% (rt: 2.54 min). 5Cca: 1H NMR (CDCl3): 0.70 and 0.76 (2d, J ) 6.6 Hz, 6H, 2 × CH3 of isobutyl), 1.07 and 1.09 (2d, J ) 6.6 and 7.0 Hz, 6H, 2 × CH3 of isopropyl), 1.43 (m, 1H, CH(CH3)2), 1.94 (m, 1H, CH(CH3)2), 2.23 (dd, J1 ) 12.5 Hz and J2 ) 9.1 Hz, 1H, 1H of CH2N), 2.35 (dd, J1 ) 12.5 Hz and J2 ) 5.9 Hz, 1H, 1H of CH2N), 3.06 (dd, J1 ) 11.7 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.21 (dd, J1 ) 11.7 Hz and J2 ) 7.9 Hz, 1H, 1H of CH2O), 3.77 (d, J ) 8.1 Hz, 1H, H4), 3.99 (d, J ) 2.9 Hz, 1H, H2), 4.18 (ABX system, 1H, H5), 7.25 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.41 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar);13C NMR (CDCl3): 15.3, 19.3, 20.7, 21.2, 27.6, 30.9, 62.5, 63.1, 70.5, 79.4, 100.6, 121.2, 129.8 (2C), 131.1 (2C), 139.4. MS: Calcd for C17H27BrNO2 [M + H]+: 356.1. Found: 356.2. Purity LCMS: >98% (rt: 2.27 min). 5Ccb: 1H NMR (CDCl3): 0.69 and 0.77 (2d, J ) 6.6 and 7.0 Hz, 6H, 2 × CH3 of isobutyl), 0.90 (t, J ) 7.0 Hz, 3H, CH3 of hexyl), 1.1-1.8 (m, 11H, CH2 of hexyl and CH(CH3)2), 2.22 (dd, J1 ) 12.5 Hz and J2 ) 9.9 Hz, 1H, 1H of CH2N), 2.37 (dd, J1 ) 12.5 Hz and J2 ) 5.5 Hz, 1H, 1H of CH2N), 3.10 (dd, J1 ) 11.7 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.16 (dd, J1 ) 11.7 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.77 (d, J ) 7.7 Hz, 1H, H4), 4.13 (dd, J1 ) 7.3 Hz and J2 ) 2.2 Hz, 1H, H2), 4.17 (td, J1 ) 7.7 Hz, J2 ) 7.7 Hz, J3 ) 4.0 Hz, 1H, H5), 7.22 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.41 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar). 13C NMR (CDCl ): 14.1, 20.6, 20.9, 22.6, 24.8, 27.6, 29.5, 3 31.9, 34.9, 62.0, 63.0, 70.1, 79.9, 97.1, 121.1, 129.8 (2C), 131.1 (2C), 139.4. MS: Calcd for C20H33BrNO2 [M + H]+: 398.2. Found: 398.2. Purity LCMS: >98% (rt: 2.53 min). 5Ccc: 1H NMR (CDCl3): 0.69 and 0.75 (2d, J ) 6.5 and 6.8 Hz, 6H, 2 × CH3 of isobutyl), 1.0-1.9 (m, 11H, CH2 of cyclohexyl and CH(CH3)2), 2.13 (m, 1H, CH of cyclohexyl), 2.24 (dd, J1 ) 12.3 Hz and J2 ) 9.1 Hz, 1H, 1H of CH2N), 2.33 (dd, J1 ) 12.3 Hz and J2 ) 5.1 Hz, 1H, 1H of CH2N), 3.06 (dd, J1 ) 11.7 Hz and J2 ) 4.1 Hz, 1H, 1H of CH2O), 3.22 (m, 1H, 1H of CH2O), 3.75 (d, J ) 7.9 Hz, 1H, H4), 3.95 (d, J ) 2.6 Hz, 1H, H2), 4.16 (td, J1 ) 8.0 Hz, J2 ) 7.7 Hz, J3 ) 4.0 Hz, 1H, H5), 7.23 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.40 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar). 13C NMR (CDCl3): 20.6, 21.1, 26.0, 26.2, 26.8, 27.6, 29.9, 30.2, 41.1, 62.5, 63.0, 70.2, 79.5, 100.3, 121.0, 129.8 (2C), 131.0 (2C), 139.5. MS: Calcd for C20H31BrNO2 [M + H]+: 396.2. Found: 396.2. Purity LCMS: 87% (rt: 2.48 min). 5Cda: 1H NMR (CDCl3): 0.97 and 1.02 (2d, J ) 6.6 and 7.3 Hz, 6H, 2 × CH3 of isopropyl), 1.75 (m, 1H, CH(CH3)2),

708 Journal of Combinatorial Chemistry, 2000, Vol. 2, No. 6

3.02 (dd, J1 ) 11.5 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.28 (dd, J1 ) 11.5 Hz and J2 ) 7.9 Hz, 1H, 1H of CH2O), 3.55 and 3.72 (2d, J ) 13.9 Hz, 2H, ArCH2N), 3.77 (s, 3H, CH3O), 3.94 (d, J ) 8.1 Hz, 1H, H4), 4.14 (m, 2H, H5 and H2), 6.74 (d, J ) 8.8 Hz, 2H, 2 × CH of Ar), 6.97 (d, J ) 8.8 Hz, 2H, 2 × CH of Ar), 7.22 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.41 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar). 13C NMR (CDCl3): 14.6, 19.1, 29.6, 53.4, 55.2, 63.3, 67.4, 78.3, 98.6, 113.4 (2C), 121.3, 128.4, 129.8 (2C), 129.9 (2C), 131.3 (2C), 136.6, 158.8. MS: Calcd for C21H27BrNO3 [M + H]+: 420.1. Found: 420.2. Purity LCMS: >98% (rt: 2.17 min). 5Cdb: 1H NMR (CDCl3): 0.89 (t, J ) 7.1 Hz, 3H, CH3 of hexyl), 1.2-1.7 (m, 10H, CH2 of hexyl), 3.08 (dd, J1 ) 11.6 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.25 (dd, J1 ) 11.6 Hz and J2 ) 7.3 Hz, 1H, 1H of CH2O), 3.54 and 3.75 (2d, J ) 14 Hz, 2H, ArCH2N), 3.77 (s, 3H, CH3O), 3.93 (d, J ) 8.1 Hz, 1H, H4), 4.14 (ABX system, 1H, H5), 4.26 (dd, J1 ) 6.3 Hz and J2 ) 2.1 Hz, 1H, H2), 6.75 (d, J ) 8.6 Hz, 2H, 2 × CH of Ar), 7.00 (d, J ) 8.6 Hz, 2H, 2 × CH of Ar), 7.23 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.43 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar). 13C NMR (CDCl3): 14.1, 22.6, 24.1, 29.3, 31.8, 34.0, 53.5, 55.2, 63.3, 67.6, 78.9, 95.4, 113.5 (2C), 121.4, 128.7, 129.9 (2C), 130.3 (2C), 131.4 (2C), 136.6, 158.8. MS: Calcd for C24H33BrNO3 [M + H]+: 462.2. Found: 462.2. Purity LCMS: >98% (rt: 2.35 min). 5Cdc: 1H NMR (CDCl3): 0.93 (tapp, J ) 7.3 Hz, 2H, 4-CH2 of cyclohexyl), 1.0-1.9 (m, 8H, CH2 of cyclohexyl), 1.96 (m, 1H, CH of cyclohexyl), 3.02 (dd, J1 ) 11.4 Hz and J2 ) 4.0 Hz, 1H, 1H of CH2O), 3.26 (dd, J1 ) 11.7 Hz and J2 ) 7.7 Hz, 1H, 1H of CH2O), 3.55 and 3.72 (2d, J ) 13.9 Hz, 2H, ArCH2N), 3.76 (s, 3H, CH3O), 3.90 (d, J ) 8.1 Hz, 1H, H4), 4.11 (d, J ) 2.2 Hz, 1H, H2), 4.12 (ABX system, 1H, H5), 6.74 (d, J ) 8.6 Hz, 2H, 2 × CH of Ar), 6.98 (d, J ) 8.6 Hz, 2H, 2 × CH of Ar), 7.21 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar), 7.41 (d, J ) 8.4 Hz, 2H, 2 × CH of Ar). 13C NMR (CDCl3): 25.4, 26.1, 26.7, 26.8, 29.8, 40.0, 53.6, 55.3, 63.2, 67.3, 78.5, 98.5, 113.3 (2C), 121.3, 128.5, 130.0 (2C), 130.4 (2C), 131.3 (2C), 136.7, 158.8. MS: Calcd for C24H31BrNO3 [M + H]+: 460.2. Found: 460.2. Purity LCMS: >98% (rt: 2.35 min). Acknowledgment. This work was supported by the NIH (GM56154, K.D.J.), The Skaggs Institute for Chemical Biology (K.D.J.), Aventis Pharmaceutical Company (K.D.J. and P.W.), and NSERC (Natural Sciences and Engineering Research Council of Canada, for a fellowship to M.R.T). The authors also thank Dr. William A. Metz of Aventis Research Center for coordinating the Aventis-Scripps collaboration. Supporting Information Available. Spectra of products. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes (1) Houghten, R. A.; Pinilla, C.; Blondelle, S. E.; Appel, J. R.; Dooley, C. T.; Cuervo, J. H. Nature 1991, 354, 84-86. (2) Jung, G.; Beck-Sickinger, A. G. Angew. Chem., Int. Ed. Engl. 1992, 31, 367-383. (3) Han, H.; Wolfe, M. M.; Brenner, S.; Janda, K. D. Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 6419-6423.

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